2.1. Introduction
Uropathogenic Escherichia coli (UPEC) is the leading cause of community-acquired urinary tract infections (UTIs). Over 100 million UTIs occur annually throughout the world, including more than 7 million cases in U.S. adolescents and adults (14). UTIs in younger children are associated with greater risk of morbidity and mortality than in older children and adults. Antimicrobial resistance among UPEC is on the rise (10, 15-18), driving efforts to discover vulnerable targets in the molecular pathogenesis of infection.
During UTI, UPEC lives in intracellular and extracellular locales. UPEC adheres to the apical bladder epithelium and invades into it (19-21). Within the bladder epithelium, UPEC typically reproduces in a biofilm-like state called intracellular bacterial communities (IBC; (5)). After maturation of IBCs, UPEC disperses away from the IBC and exits the infected cells. Extracellular UPEC must then re-adhere, initiating the invasion and intracellular reproduction phases again. Past studies have revealed bacteria encased in the IBC within a complex matrix of fibrous protein assemblies and polysaccharides (5). Our prior studies have also shown that disruption of the IBC pathway aborts experimental UTI, highlighting the importance of this intracellular lifecycle (22-25). A detailed study of urine samples from women with acute UTI demonstrated IBC in shed bladder epithelial cell, showing that the pathway is conserved in humans (26).
Investigators have found that bacterial encapsulation is an important UPEC virulence factor (4-6), and experiments show that the K capsule contributes to multiple aspects of pathogenesis, including IBC formation. K capsules, also called K antigens, are enveloping structures composed of high-molecular-weight polysaccharides. Among UPEC, the K antigens K1, K2, K5, K30, and K92 are thought to be most prevalent (27). Capsules are well-established virulence factors for a variety of pathogens that are thought to protect the cell from opsonophagocytosis and complement-mediated killing (reviewed in (28, 29)). While they did not study the effects of K antigen from UPEC, Llobet et al. recently demonstrated that the highly acidic polysaccharide capsules of diverse organisms including Klebsiella pneumoniae, Pseudomonas aeruginosa, and Streptococcus pneumoniae interact strongly with APs, acting as “sponges” to sequester and neutralize the APs (30).
Of the different K types, the Group 2 and Group 3 capsules are most prevalent among UPEC isolates, with K1 and K5 being leading types. Although the capsules have different compositions, they are regulated, synthesized, assembled, and exported by functionally homologous factors, leading us to hypothesize that we can develop small molecular inhibitors of K-type encapsulation that target the most medically important K capsule types. Furthermore, the medically important infectious agents Campylobacter jejuni, Haemophilus influenzae, Neisseria meningitides, and Salmonella typhimurium among others, use homologous components in the biogenesis of their capsules. The K1 capsule type is closely associated with pathogenic isolates; not only is it the leading type in UTI, but it also accounts for much of the extra-urinary tract complications. Animals studies of E. coli K1 sepsis demonstrated that injection of a K1 capsule degrading enzyme abrogates infection (7). However, the enzyme treatment is immunogenic; accordingly, chemical inhibition may prove to be a superior approach.
There are currently no therapeutics that specifically inhibit the formation of any bacterial capsule, and this is a novel strategy for preventing or decreasing the prevalence of chronic or re-occurring urinary tract infections. New insights into the roles of K1 capsules in UPEC virulence during UTI make capsules an attractive target for therapeutic intervention. Antimicrobial resistance among UPEC is on the rise (11, 12, 15, 31, 32), and the discovery of novel small molecules that can act as probes or lead compounds for the investigation and treatment of UTI will add to the arsenal of compounds available for single or combination therapies.